Frontotemporal dementia support

Genetic Testing

Dr Edward Wild & Katy Judd, Dementia Research Centre

Updated May 2012 & May 2015 by Dr Selina Wray, UCL Institute of Neurology

In most patients (50-70%), frontotemporal dementia (FTD) is a sporadic disease. This means that FTD occurs in an individual person by chance, without anyone else in the family having been affected. Relatives of a patient with sporadic disease have the same risk of developing FTD as the general population, i.e. they are not at increased risk.

However, in some cases FTD appears to run in families, suggesting there is a genetic component. The genetics of FTD are complex, and not yet fully understood, but research groups around the world are continuously advancing our knowledge with many new developments in recent years.

The largest groups of patients with a genetic component (20-40%) will have other family members who have also had a diagnosis of either FTD or a related neurodegenerative disorder, such as Alzheimer’s disease or Motor Neuron Disease. However, the disease is not passed down from parent to child in these families. This type of dementia is termed familial, and these patients may carry genetic risk variants that increase the risk of developing disease but are not sufficient to cause FTD alone. The inheritance pattern in familial disease is complex and likely due to a combination of genes, lifestyle and environment. Some family members may carry the risk gene and remain completely unaffected. The genes that increase the risk of developing disease are only just starting to be discovered, and because the link between these genes and dementia is not clear there is currently no genetic testing available for risk genes.

In a smaller number of families (~10%), dementia is caused by a genetic fault. This type of dementia is called inherited dementia, and there is a clear family history of disease being passed from parent to child. Specifically, every patient will have an affected parent, and each child of an affected person will have a 50% chance of developing the disease. Several genes have been identified with genetic faults that cause FTD.

Understanding Inherited Dementia

A gene is like a set of instructions, and each gene instructs the cell how to make a particular protein. Every cell of our bodies contains two copies of every gene, one inherited from each parent. Genetic diseases can occur when there is a mistake (a mutation) in the gene, resulting in the production of a faulty protein that cannot carry out its normal function. Depending on the protein, and the nature of the mistake, one or both copies of the gene may need to be faulty to cause a disease.

All the mutations discovered so far which cause FTD are “autosomal dominant”, meaning that only one faulty copy of the gene is needed to develop the disease. The risk of passing the faulty copy to children in autosomal dominant disorders is 50% (1 in 2 chance) for each pregnancy. Typically, in inherited FTD the patients become affected at an earlier age and have a more severe form of disease than in sporadic patients. However, with some mutations, for reasons we don’t fully understand, it is possible to have the gene and still not develop signs of the disease.

There are 3 main genes that have been identified that can cause Frontotemporal dementia in an autosomal dominant way: tau, progranulin and C9ORF72.

Understanding why changes in tau, progranulin and C9ORF72 cause dementia is the focus of research in laboratories around the world, because understanding how these proteins cause brain cells to die could be the key to developing new treatments for FTD. Some families may have genetic disease without carrying a mutation in tau, progranulin or C9ORF72 and research groups worldwide are also trying to identify new genes that with cause or increase risk for dementia.

Does it skip a generation?

There is usually a strong family history of the illness and you may know of cousins, aunts/uncles and grandparents who are affected. The disease may appear to skip a generation if a person with the faulty gene dies of another cause before the illness develops.

If I inherit the gene, will I get the disease?

If you have an abnormal gene, you will probably develop the disease if you live long enough. However, having the abnormal gene does not always predict when you will get symptoms, or how rapidly the disease may progress. A minority of people with an abnormal gene may never get symptoms.

Genetic counselling and testing

The medical team will ask about family history of similar illnesses. If they are concerned that the illness may be inherited, they can test for known mutations. Where tests are available, it often takes several months to get a result. The person’s next of kin would be included in the counselling and testing process. Specific consent is needed to perform genetic tests.

If the precise mutation is not known, researchers may be interested in identifying it, and will need DNA from several affected family members. Identifying a new mutation takes many months or years and is not always possible.

If the precise mutation affecting someone is known, it is sometimes possible to test the person’s adult children to see whether they have inherited it, to give an idea of whether they will develop the disease. Being tested is a very difficult decision with no right or wrong answer, and counselling and support is available throughout the process.

If you are thinking about finding out whether you have inherited a faulty gene, please ask your GP or hospital consultant to refer you to a Regional Genetics Clinic. It will be helpful to discuss this with the medical team caring for you first.

Read about one person’s experience about having the genetic test for frontotemporal dementia